Abstract | BACKGROUND: METHODS: We studied this in human lung epithelial cell lines and primary bronchial epithelial cells (PBEC) from COPD patients and control (non-)smokers, at baseline and on cigarette smoke extract (CSE) exposure. RESULTS: CSE significantly decreased WNT-4, WNT-10B and FZD2 and increased WNT-5B mRNA expression in 16HBE, but did not affect WNT-4 protein. The mRNA expression of WNT-4, but not other WNT ligands, was lower in PBEC from smokers than non-smokers and downregulated by CSE in PBEC from all groups, yet higher in PBEC from COPD patients than control smokers. Moreover, PBEC from COPD patients displayed higher WNT-4 protein expression than both smokers and non-smokers. Exogenously added WNT-4 significantly increased CXCL8/IL-8, IL-6, CCL5/ RANTES, CCL2/MCP-1 and vascular endothelial growth factor ( VEGF) secretion in 16HBE, but did not affect the canonical WNT target genes MMP-2, MMP-9, fibronectin, β- catenin, Dickkopf and axin-2, and induced activation of the non-canonical signalling molecule p38. Moreover, WNT-4 potentiated the CSE-induced upregulation of IL-8 and VEGF. CONCLUSIONS: WNT-4 mRNA and protein levels are higher in PBEC from COPD patients than control (non-)smokers, while cigarette smoke downregulates airway epithelial WNT-4 mRNA, but not protein expression. As WNT-4 further increases CSE-induced pro-inflammatory cytokine release in bronchial epithelium, we propose that higher epithelial WNT-4 levels in combination with cigarette smoking may have important implications for the development of airway inflammation in COPD.
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Authors | Irene H Heijink, Harold G de Bruin, Maarten van den Berge, Lisa J C Bennink, Simone M Brandenburg, Reinoud Gosens, Antoon J van Oosterhout, Dirkje S Postma |
Journal | Thorax
(Thorax)
Vol. 68
Issue 8
Pg. 709-16
(Aug 2013)
ISSN: 1468-3296 [Electronic] England |
PMID | 23370438
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- FZD2 protein, human
- Frizzled Receptors
- Proto-Oncogene Proteins
- RNA, Messenger
- WNT10B protein, human
- WNT4 protein, human
- WNT5B protein, human
- Wnt Proteins
- Wnt4 Protein
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Topics |
- Adult
- Aged
- Cell Line
- Epithelial Cells
(metabolism, pathology)
- Female
- Frizzled Receptors
(biosynthesis, genetics)
- Gene Expression Regulation
- Humans
- Male
- Middle Aged
- Proto-Oncogene Proteins
(biosynthesis)
- Pulmonary Disease, Chronic Obstructive
(genetics, metabolism, pathology)
- RNA, Messenger
(genetics)
- Respiratory Mucosa
(metabolism, pathology)
- Signal Transduction
- Smoking
(adverse effects)
- Wnt Proteins
(biosynthesis, genetics)
- Wnt4 Protein
(biosynthesis, genetics)
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